Despite advances in antibiotic therapy and cardiopulmonary support, septic shock remains a highly lethal disease. Septic is the leading cause of death in trauma and immunosuppressed patients hospitalized in intensive care units. Recent evidence suggests that interleukin-1 (IL-1) and tumor necrosis factor (TNF) release by host defense systems may contribute to tissue injury, organ failure, and death associated with septic shock. Both of these cytokines have been shown to be increased in the blood from septic animal models and from humans with sepsis, and infusion of these molecules into normal animals produces tissue injury and organ dysfunction similar to that occurring during human sepsis. The pathophysiology of sepsis induced tissue injury is complex and most certainly includes the interplay of a variety of mediators. Understanding the importance of specific mediators in the pathogenesis of sepsis, and the development of effective therapies with which to modify such mediators, will require the formulation of specific mediator antagonists. A new potential form of specific mediator antagonist has recently been suggested by research showing that cellular cytokine receptors also exist in smaller modified soluble forms. These smaller soluble receptors maintain the capacity to specifically bind with associated cytokines and presumably represent a regulatory system which binds and either temporarily or permanently inactivates circulating cytokines. Soluble IL-1 and TNF receptors have been identified and their structures determined. Human recombinant soluble IL-1 and TNF receptors are presently available for study in animal models of sepsis. Because these are human proteins, optimum evaluation of their effects during sepsis would be obtained in nonhuman primate models. We have presently shown that endotoxin challenge in a rhesus monkey model produces temperature, hemodynamic and hematologic changes very similar to those occurring in endotoxin infused human studies. We are at this time studying the effects of administration of both recombinant human IL-1 and TNF receptor in this endotoxin challenged nonhuman primate model.